U.S. patent application number 12/394308 was filed with the patent office on 2010-01-28 for tablets and preparation thereof.
This patent application is currently assigned to ABBOTT LABORATORIES. Invention is credited to Martin Bultmann, Lynn V. Faitsch, Nishanth Gopinathan, John B. Morris, Albert Santiago, Heinz Schlayer, Rudolf Schroeder, Jacqueline Wardrop.
Application Number | 20100021540 12/394308 |
Document ID | / |
Family ID | 40636918 |
Filed Date | 2010-01-28 |
United States Patent
Application |
20100021540 |
Kind Code |
A1 |
Gopinathan; Nishanth ; et
al. |
January 28, 2010 |
Tablets and Preparation Thereof
Abstract
The present invention features processes of making tablets
having reduced internal fractures. In one aspect, the processes
comprise the steps of (1) compressing a pre-tabletting material in
a die to form a tablet, where an internal surface of the die is
lubricated with at least one lubricant and the pre-tabletting
material comprises at least one therapeutic agent and at least one
pharmaceutically acceptable polymer; and (2) ejecting said tablet
from said die. In another aspect, the processes employ a granular
or powdery pre-tabletting material which comprises at least one
therapeutic agent and at least one pharmaceutically acceptable
polymer, wherein 90% of the particles in the pre-tabletting
material are smaller than 400 .mu.m.
Inventors: |
Gopinathan; Nishanth;
(Wadsworth, IL) ; Schroeder; Rudolf; (Worms,
DE) ; Santiago; Albert; (Beach Park, IL) ;
Faitsch; Lynn V.; (Libertyville, IL) ; Wardrop;
Jacqueline; (Wilmette, IL) ; Morris; John B.;
(Grayslake, IL) ; Bultmann; Martin; (Oftersheim,
DE) ; Schlayer; Heinz; (Freinsheim, DE) |
Correspondence
Address: |
PAUL D. YASGER;ABBOTT LABORATORIES
100 ABBOTT PARK ROAD, DEPT. 377/AP6A
ABBOTT PARK
IL
60064-6008
US
|
Assignee: |
ABBOTT LABORATORIES
Abbott Park
IL
|
Family ID: |
40636918 |
Appl. No.: |
12/394308 |
Filed: |
February 27, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61032145 |
Feb 28, 2008 |
|
|
|
Current U.S.
Class: |
424/464 ;
264/330; 514/274; 514/365 |
Current CPC
Class: |
A61K 31/513 20130101;
A61K 9/2018 20130101; A61K 9/2095 20130101; A61K 31/513 20130101;
A61K 31/427 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 9/2013 20130101; A61K 9/2027 20130101; A61K 31/427 20130101;
A61J 3/10 20130101 |
Class at
Publication: |
424/464 ;
514/365; 264/330; 514/274 |
International
Class: |
A61K 31/427 20060101
A61K031/427; A61K 9/20 20060101 A61K009/20; B29C 67/24 20060101
B29C067/24; A61K 31/513 20060101 A61K031/513 |
Claims
1. A process of making tablets, comprising: compressing a
pre-tabletting material in a die to form a tablet, wherein an
internal surface of the die is lubricated with at least one
lubricant, and said pre-tabletting material comprises at least one
therapeutic agent and at least one pharmaceutically acceptable
polymer; and ejecting said tablet from said die, wherein said
pre-tabletting material does not include (1) any therapeutic agent
that is denaturalized or inactivated when compressed at a pressure
of greater than or equal to 1 ton/cm.sup.2, (2) any low molecule
active ingredient the elution of which is delayed when compressed
at a pressure of greater than or equal to 1 ton/cm.sup.2, or (3)
any therapeutic agent that is affected by said at least one
lubricant.
2. The process according to claim 1, wherein said pre-tabletting
material comprises a solid dispersion of said therapeutic agent in
a matrix, and said matrix comprises said pharmaceutically
acceptable polymer.
3. The process according to claim 2, wherein said pre-tabletting
material comprises at least 30% by weight of said at least one
pharmaceutically acceptable polymer.
4. The process according to claim 3, wherein said matrix further
comprises at least one pharmaceutically acceptable surfactant.
5. The process according to claim 4, wherein said pharmaceutically
acceptable polymer is a homopolymer or copolymer of N-vinyl
pyrrolidone, and said pharmaceutically acceptable surfactant has an
HLB value of from 4 to 10.
6. The process according to claim 5, wherein said pharmaceutically
acceptable polymer is copovidone, and said pharmaceutically
acceptable surfactant is sorbitan monolaurate.
7. The process according to claim 6, wherein said therapeutic agent
is ritonavir.
8. The process according to claim 7, wherein said pre-tabletting
material further comprises lopinavir.
9. The process according to claim 7, wherein said at least one
lubricant comprises sodium stearyl fumarate.
10. The process according to claim 9, wherein said pre-tabletting
material is compressed in the die between a lower surface of an
upper punch and an upper surface of a lower punch, and said lower
surface and said upper surface are lubricated with said at least
one lubricant.
11. The process according to claim 7, wherein said tablet shows a
dose-adjusted AUC of ritonavir plasma concentration in dogs, under
non-fasting conditions, of at least 5 .mu.gh/ml/100 mg.
12. The process according to claim 8, wherein said tablet shows a
dose-adjusted AUC of ritonavir plasma concentration in dogs, under
non-fasting conditions, of at least 5 .mu.gh/ml/100 mg, and a
dose-adjusted AUC of lopinavir plasma concentration in dogs, under
non-fasting conditions, of at least 15 .mu.gh/ml/100 mg.
13. The process according to claim 3, wherein said pre-tabletting
material is prepared by melt extrusion which comprises the steps of
solidifying a melt comprising said at least one therapeutic agent
and said at least one pharmaceutically acceptable polymer; and
milling said solidified melt to provide said pre-tabletting
material.
14. The process according to claim 3, wherein said at least one
therapeutic agent comprises an anti-cancer or anti-pain agent.
15. A process of making tablets, comprising: compressing a granular
or powdery pre-tabletting material in a die to form a tablet,
wherein said granular or powdery material comprises at least one
therapeutic agent and at least one pharmaceutically acceptable
polymer, and at least 90% of particles in said granular or powdery
material are smaller than 400 .mu.m; and ejecting said tablet from
said die.
16. The process according to claim 15, wherein said pre-tabletting
material comprises a solid dispersion of said at least one
therapeutic agent in a matrix, and said matrix comprises said at
least one pharmaceutically acceptable polymer.
17. The process according to claim 16, wherein said at least one
therapeutic agent comprises ritonavir, or a combination of
ritonavir and lopinavir.
18. A tablet comprising a solid dispersion of at least one
therapeutic agent in a matrix, wherein said matrix comprises at
least one pharmaceutically acceptable hydrophilic polymer and
optionally, at least one pharmaceutically acceptable surfactant,
wherein said tablet does not contain any lubricant, or the total
amount of lubricant or lubricants in said tablet is less than 0.5%
by weight of said tablet, and wherein said tablet does not contain
(1) any therapeutic agent that is denaturalized or inactivated when
compressed at a pressure of greater than or equal to 1
ton/cm.sup.2, (2) any low molecule active ingredient the elution of
which is delayed when compressed at a pressure of greater than or
equal to 1 ton/cm.sup.2, or (3) any therapeutic agent that is
affected by said lubricant or lubricants.
19. A tablet comprising a compressed core which includes a solid
dispersion of at least one therapeutic agent in a matrix, wherein
said matrix comprises at least one pharmaceutically acceptable
hydrophilic polymer and optionally, at least one pharmaceutically
acceptable surfactant, wherein said core does not contain any
lubricant therein, and said tablet does not contain (1) any
therapeutic agent that is denaturalized or inactivated when
compressed at a pressure of greater than or equal to 1
ton/cm.sup.2, (2) any low molecule active ingredient the elution of
which is delayed when compressed at a pressure of greater than or
equal to 1 ton/cm.sup.2, or (3) any therapeutic agent that is
affected by any lubricant comprised in said tablet.
20. A pre-tabletting material comprising at least one therapeutic
agent and at least one pharmaceutically acceptable polymer; wherein
said pre-tabletting material does not contain any lubricant, or the
total amount of lubricant or lubricants in said pre-tabletting
material is less than 0.5% by weight of said pre-tabletting
material, and wherein said pre-tabletting material does not include
(1) any therapeutic agent that is denaturalized or inactivated when
compressed at a pressure of greater than or equal to 1
ton/cm.sup.2, (2) any low molecule active ingredient the elution of
which is delayed when compressed at a pressure of greater than or
equal to 1 ton/cm.sup.2, or (3) any therapeutic agent that is
affected by said at least one lubricant.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 61/032,145, filed on Feb. 28, 2008, the entire
content of which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to tablet dosage forms and
processes of making the same.
BACKGROUND
[0003] A typical method of making tablets involves compressing a
mixture of active pharmaceutical ingredient(s) and excipient(s) in
a die or mold to give the tablet the desired shape and hardness. A
common mechanical unit in tablet compression equipment includes a
lower punch, which fits into the die from the bottom, and an upper
punch, which enters the die cavity from the top. The tablet is
compressed by pressure applied on punches.
[0004] Lubricants can be added to the pre-tabletting mixture to
help reduce the frictional wear of the die and its associated
parts. Binders can also be added to help promote the adhesion of
different ingredients in the mixture. Disintegrants help the tablet
to disintegrate in vivo and thus help deliver the active
pharmaceutical ingredient(s) contained in the tablet. A tablet can
also be made by tightly compressing active pharmaceutical
ingredient(s) without using any excipients.
[0005] It is sometimes desirable to coat the tablet. The coating
may, for example, be a thin film to prevent decomposition of the
tablet. The film may also have other purposes such as to mask a
tablet's unpleasant taste or to delay the disintegration or
dissolution of a tablet.
[0006] A more detailed description of tablets and their preparation
can be found in E. Rudnic and J. Schwartz, "Oral Solid Dosage
Forms," REMINGTON'S PHARMACEUTICAL SCIENCE (18th edition, 1990),
chapter 89, pp. 1633-1658, the entire content of which is
incorporated herein by reference.
SUMMARY OF THE INVENTION
[0007] The present invention features processes of making tablets
in a lubricated die. The present invention is based on an
unexpected finding that a polymer-containing, pre-tabletting
material, when blended with lubricants and compressed in an
unlubricated die, may form tablets containing internal fractures.
These internal fractures are precursors to development of major
tablet quality defects such as capping or lamination. The use of a
lubricated die surprisingly reduces or eliminates these internal
fractures, thereby creating tablets having improved structural
stability and physical integrity.
[0008] Using a lubricated die also reduces or eliminates internal
fractures in tablets which are made from pre-tabletting materials
that are not blended with any lubricants before compression.
Therefore, the present invention features a tabletting process that
does not require lubricant blending before compression.
Under-blending and over-blending are common issues associated with
the lubricant blending process. For instance, over-blending can
lead to a physical alignment or "coating" of blended particles with
a layer of lubricant. This can lead to delayed dissolution
profiles, reduced tablet hardness, increased coating defects, or
deteriorated in vivo results. The use of a lubricated die allows
for the elimination of the lubricant blending process while
improving the physical integrity and product quality of the
resulting tablets. By eliminating lubricant blending, the new
process reduces operation steps, which in turn can improve
manufacturing cycle time, simplify implementation of a continuous
manufacturing process, enhance process throughput, and reduce
manufacturing costs. Moreover, the improved physical integrity of
the resulting tablets can reduce the potential for further
development of tablet defects during the more robust downstream
operations such as coating and bin transport.
[0009] In one aspect, the present invention features a process of
making tablets, the process comprising the steps of: [0010]
compressing a pre-tabletting material in a die to form a tablet,
wherein at least one internal surface of the die is lubricated with
at least one lubricant, and the pre-tabletting material comprises
at least one therapeutic agent and at least one pharmaceutically
acceptable polymer; and [0011] ejecting the tablet from the die.
The pre-tabletting material does not include (1) any therapeutic
agent that is denaturalized or inactivated when compressed at a
pressure of greater than or equal to 1 ton/cm.sup.2, (2) any low
molecule active ingredient the elution of which is delayed when
compressed at a pressure of greater than or equal to 1
ton/cm.sup.2, or (3) any therapeutic agent that is affected by said
at least one lubricant.
[0012] Preferably, the process does not include any lubricant
blending step. The pre-tabletting material also preferably does not
comprise any lubricant, or contains only an insignificant amount of
lubricant(s). In many cases, the pre-tabletting material comprises
less than 0.5% by weight of lubricant(s). More preferably, the
pre-tabletting material comprises less than 0.2%, 0.1%, 0.05%,
0.01% or lesser by weight of lubricant(s).
[0013] The pre-tabletting material can comprise, for example and
without limitation, at least 30% by weight of said at least one
pharmaceutically acceptable polymer (including a blend of two or
more pharmaceutically acceptable polymers). For instance, the
pre-tabletting material can comprise at least 40%, 50%, 60%, 70% or
80% by weight of said at least one pharmaceutically acceptable
polymer. The present invention also contemplates the use of
pre-tabletting materials that contain less than 30% by weight of
said at least one pharmaceutically acceptable polymer. For
instance, the pre-tabletting material can comprise at least 25%,
20%, 15% or 10% by weight of said at least one pharmaceutically
acceptable polymer.
[0014] In one embodiment, each of said at least one
pharmaceutically acceptable polymer is hydrophilic (or
water-soluble). Preferably, each of said at least one
pharmaceutically acceptable polymer has a Tg of at least 50.degree.
C. Non-limiting examples of suitable polymers include homopolymers
or copolymers of N-vinyl pyrrolidone, such as copovidone, or
hydroxypropyl methylcellulose (HPMC).
[0015] Polymers that are water-insoluble or poorly water-soluble
can also be used.
[0016] Any suitable lubricant can be used in the present invention.
A non-limiting example of a preferred lubricant is sodium stearyl
fumarate.
[0017] Where the pre-tabletting material is compressed by a lower
punch and an upper punch, the upper surface of the lower punch
and/or the lower surface of the upper punch can also be lubricated.
The die and the punches can be lubricated with the same
lubricant(s) or different lubricants.
[0018] In one embodiment, the therapeutic agent(s) comprised in the
pre-tabletting material is formulated as a solid dispersion in a
matrix which comprises said at least one pharmaceutically
acceptable polymer. Where the pre-tabletting material comprises two
or more therapeutic agents, the agents can be formulated in the
same solid dispersion or different solid dispersions.
[0019] The matrix can further comprise at least one
pharmaceutically acceptable surfactant. In one embodiment, each of
said at least one pharmaceutically acceptable surfactant has an HLB
value of from 4 to 10. Preferably, said at least one
pharmaceutically acceptable surfactant comprises a sorbitan mono
fatty acid ester, such as sorbitan monolaurate.
[0020] In one embodiment, the pre-tabletting material comprises
ritonavir, or a combination of ritonavir and lopinavir. The tablet
made from this pre-tabletting material preferably shows a
dose-adjusted AUC of ritonavir plasma concentration in dogs, under
non-fasting conditions, of at least 5 .mu.gh/ml/100 mg, and/or a
dose-adjusted AUC of lopinavir plasma concentration in dogs, under
non-fasting conditions, of at least 15 .mu.gh/ml/100 mg. In another
embodiment the pre-tabletting material comprises ritonavir and
another therapeutic agent which is metabolized by cytochrome P450
oxidase (e.g., CYP3A4) or transported by P-glycoprotein.
[0021] In still another embodiment, the present invention features
a process of making tablets, the process comprising the steps of:
[0022] compressing a pre-tabletting material in a die to form a
tablet, wherein an internal surface of the die is lubricated with
at least one lubricant, and the pre-tabletting material comprises a
solid dispersion of at least one therapeutic agent in a matrix,
said matrix comprising at least one pharmaceutically acceptable
polymer, and said at least one therapeutic agent comprising
ritonavir; and [0023] ejecting the tablet from the die. The
pre-tabletting material can comprise, for example, at least 30%,
40%, or 50% by weight of said at least one pharmaceutically
acceptable polymer. Preferably, each of said at least one
pharmaceutically acceptable polymer is hydrophilic (or
water-soluble) and has a Tg of at least 50.degree. C. More
preferably, said at least one pharmaceutically acceptable polymer
comprises copovidone. The matrix may further comprise at least one
pharmaceutically acceptable surfactant. Without limitation, each of
said at least one pharmaceutically acceptable surfactant preferably
has an HLB value of from 4 to 10. A non-limiting example of a
preferred surfactant is sorbitan monolaurate.
[0024] The pre-tabletting material employed in the present
invention can be prepared by a variety of means known in the art,
such as melt-extrusion, spray drying, freeze drying, solvent
evaporation, wet granulation, dry granulation, direct blend, and
fluidized bed granulation. One of the preferred methods is melt
extrusion which comprises the steps of: [0025] solidifying a melt
comprising the therapeutic agent(s) and said at least one
pharmaceutically acceptable polymer; and [0026] milling the
solidified melt to provide the pre-tabletting material.
[0027] The present invention also features a tabletting process
using a pre-tabletting material that has reduced particle sizes.
Where a pre-tabletting material contains granules of small sizes
and is compressed at a relatively low pressure, the resulting
tablets surprisingly contain significantly less or no detectable
internal fractures, even when the compression is carried out in an
unlubricated die and using unlubricated punches. Accordingly, in
another aspect the present invention features another process of
making tablets, the process comprising the steps of: [0028]
compressing a granular or powdery material in a die to form a
tablet, wherein said granular or powdery material comprises at
least one therapeutic agent and at least one pharmaceutically
acceptable polymer, and at least 90% of particles in said granular
or powdery material are smaller than 400 .mu.m; and [0029] ejecting
said tablet from said die.
[0030] In one embodiment, 90% of the particles in the granular or
powdery material is smaller than 300 .mu.m, such as smaller than
200 .mu.m, or smaller than 100 .mu.m. The present invention also
contemplates the use of a pre-tabletting material where the mean
particle size of the pre-tabletting material is no greater than 200
.mu.m, preferably no greater than 150 .mu.m, and more preferably no
greater than 100 .mu.m. Any pre-tabletting material described
herein can be subject to particle size reduction and then used to
make tablets with reduced or eliminated internal fractures.
[0031] Furthermore, the present invention features tablets made
according to the processes of the present invention. In one
embodiment, the tablet comprises a solid dispersion of at least one
therapeutic agent in a matrix, wherein the matrix comprises at
least one pharmaceutically acceptable hydrophilic polymer (or at
least one pharmaceutically acceptable water-soluble polymer) and
optionally, at least one pharmaceutically acceptable surfactant,
wherein the tablet does not contain any lubricant, or the total
amount of lubricant or lubricants in the tablet is less than 0.5%
by weight of the tablet, and wherein the tablet does not contain
(1) any therapeutic agent that is denaturalized or inactivated when
compressed at a pressure of greater than or equal to 1
ton/cm.sup.2, (2) any low molecule active ingredient the elution of
which is delayed when compressed at a pressure of greater than or
equal to 1 ton/cm.sup.2, or (3) any therapeutic agent that is
affected by said lubricant or lubricants. In many cases, the tablet
does not contain any lubricant, or the total amount of lubricant or
lubricants in the tablet is less than 0.25%, 0.1%, 0.05%, 0.01% or
lesser by weight of the tablet. The therapeutic agent(s) formulated
in the tablet may comprise, for example and without limitation,
ritonavir, or a combination of ritonavir and another therapeutic
agent (e.g., a combination of ritonavir and lopinavir, or a
combination of ritonavir and another therapeutic agent that is
metabolized by CYP3A4 or transported by P-glycoprotein).
[0032] In another embodiment, a tablet made according to the
present invention comprises a compressed core which includes a
solid dispersion of at least one therapeutic agent in a matrix,
wherein the matrix comprises at least one pharmaceutically
acceptable hydrophilic polymer (or at least one pharmaceutically
acceptable water-soluble polymer) and optionally, at least one
pharmaceutically acceptable surfactant, and wherein the core does
not contain any lubricant therein, and the tablet does not contain
(1) any therapeutic agent that is denaturalized or inactivated when
compressed at a pressure of greater than or equal to 1
ton/cm.sup.2, (2) any low molecule active ingredient the elution of
which is delayed when compressed at a pressure of greater than or
equal to 1 ton/cm.sup.2, or (3) any therapeutic agent that is
affected by a lubricant comprised in said tablet (if any). The core
can be coated with a film coat. Residual lubricant(s) may be
detectable in the tablet as a result of contamination from
lubricated die and/or punches. The therapeutic agent(s) formulated
in the tablet may comprise, for example and without limitation,
ritonavir, or a combination of ritonavir and another therapeutic
agent (e.g., a combination of ritonavir and lopinavir, or a
combination of ritonavir and another therapeutic agent that is
metabolized by CYP3A4 or transported by P-glycoprotein).
[0033] Other features, objects, and advantages of the present
invention are apparent in the detailed description that follows. It
should be understood, however, that the detailed description, while
indicating preferred embodiments of the invention, are given by way
of illustration only, not limitation. Various changes and
modifications within the scope of the invention will become
apparent to those skilled in the art from the detailed
description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0034] The drawings are provided for illustration, not
limitation.
[0035] FIG. 1 schematically depicts a 4-step tabletting cycle
comprising on-line lubrication (Step 1), die filling (Step 2),
tablet compression (Step 3), and tablet ejection (Step 4).
[0036] FIG. 2A shows the particle size distribution of the target
milled extrudate.
[0037] FIG. 2B illustrates the particle size distribution of the
fine extrudate, which was separated from the coarse extrudate by
sieving the target milled extrudate using 170 micron mesh.
[0038] FIG. 2C depicts the particle size distribution of the coarse
extrudate.
[0039] FIG. 3 illustrates the mean yield pressure for different
formulations.
[0040] FIG. 4A demonstrates the X-ray microtomography (XMT) image
of a tablet made of the target milled extrudate and compressed at
36 kN load without die wall lubrication.
[0041] FIG. 4B shows the XMT image of a tablet made of the target
milled extrudate and compressed at 42 kN load without die wall
lubrication.
[0042] FIG. 4C describes the XMT image of a tablet made of the
target milled extrudate and compressed at 48 kN load without die
wall lubrication.
[0043] FIG. 4D shows the XMT image of a tablet made of the target
milled extrudate and compressed at 42 kN load with die wall
lubrication.
[0044] FIG. 4E demonstrates the XMT image of a tablet made of the
target milled extrudate and compressed at 48 kN load with die wall
lubrication.
[0045] FIG. 5A shows the XMT images of a tablet made of the fine
extrudate and compressed at 36 kN without die wall lubrication.
[0046] FIG. 5B illustrates the XMT images of a tablet made of the
fine extrudate and compressed at 36 kN with die wall
lubrication.
[0047] FIG. 6A shows the XMT images of a tablet made of the fine
extrudate and compressed at 42 kN without die wall lubrication.
[0048] FIG. 6B depicts the XMT images of a tablet made of the fine
extrudate and compressed at 42 kN with die wall lubrication.
[0049] FIG. 7A illustrates the XMT images of a tablet made of the
fine extrudate and compressed at 48 kN without die wall
lubrication.
[0050] FIG. 7B illustrates the XMT images of a tablet made of the
fine extrudate and compressed at 48 kN with die wall
lubrication.
[0051] FIG. 8A shows the XMT images of a tablet made of the coarse
extrudate and compressed at 42 kN without die wall lubrication.
[0052] FIG. 8B shows the XMT images of a tablet made of the coarse
extrudate and compressed at 42 kN with die wall lubrication.
[0053] FIG. 9 depicts the XMT images of a tablet made of the coarse
extrudate and compressed at 48 kN with die wall lubrication.
DETAILED DESCRIPTION
[0054] The present invention features tablets having reduced or
eliminated internal fractures. The present invention also features
tabletting processes including the step of compressing a
pre-tabletting material in a lubricated die. This aspect of the
invention is based on an unexpected finding that a
polymer-containing, pre-tabletting material, when compressed at
high pressures in an unlubricated die, forms tablets containing
internal fractures that may cause mechanical failures such as
capping and/or delamination. When the same material (either blended
or not blended with lubricants) is compressed in a lubricated die,
the resulting tablets contain significantly less or no detectable
internal fractures. By reducing the particle sizes of the
pre-tabletting material, the present invention also surprisingly
found that the resulting tablets contain significantly less or no
detectable internal fractures.
[0055] Capping and delamination are defects that are often not
discovered until coating or packaging. The present invention used a
non-invasive method to predict the capping or delamination tendency
of a tablet. The method employs X-ray microtomography (XMT) to
image the internal structure of the tablet. The presence of
internal fractures in the tablet is often indicative of an
increased risk of capping or lamination. Using XMT, it was
unexpectedly found that when a polymer-containing, pre-tabletting
material is compressed in an unlubricated die, the resulting
tablets contain a notable amount of internal fractures, which
substantially increase the capping or delamination risk of the
tablets. It was surprisingly found that by lubricating the die wall
before compression, the internal fractures in the tablets could be
significantly reduced or eliminated, leading to improved physical
integrity and physical stability of the tablets.
[0056] Accordingly, the present application features a process of
making tablets comprising the steps of: [0057] compressing a
pre-tabletting material in a die to form a tablet, wherein an
internal surface of the die is lubricated with at least one
lubricant, and the pre-tabletting material comprises at least one
therapeutic agent and at least one pharmaceutically acceptable
polymer; and [0058] releasing or ejecting the tablet from the
die.
[0059] The lubricated internal surface of the die is in contact
with the pre-tabletting material or the tablet at least at one
point during compression or ejection. In many instances, the
lubricated internal surface of the die is in contact with the
pre-tabletting material throughout tablet compression, or is in
contact with the tablet throughout tablet ejection. Preferably, the
entire internal surface of the die that is in contact with the
pre-tabletting material and the tablet during compression and
ejection is lubricated.
[0060] A common mechanical unit in tablet compression equipment
includes two punches which operate within the die cavity. The
pre-tabletting material, often in granular or powdery forms, is
filled into the die cavity and then compressed by the punches under
a pre-determined pressure to form a tablet. The surfaces of the
punches that are in contact with the pre-tabletting material during
compression are herein referred to as the compression surfaces. The
compression surface(s) can be engraved or embossed with symbols,
initials, or other design patterns. Where the two punches are
aligned vertically, they are referred to as the lower punch and the
upper punch, respectively, depending on their locations relative to
the die. The lower punch enters the die from the bottom, and the
upper punch enters the die from the top. The compression surface of
the lower punch is herein referred to as the upper surface of the
lower punch, and the compression surface of the upper punch is
herein referred to as the lower surface of the upper punch.
[0061] According to the present invention, at least one compression
surface of the two punches (e.g., the upper surface of the lower
punch, or the lower surface of the upper punch) can also be
lubricated before die fill. Preferably, both of the compression
surfaces (e.g., both the upper surface of the lower punch and the
lower surface of the upper punch) are lubricated.
[0062] In one embodiment, the internal surface of the die that is
contact with the pre-tabletting material during compression and/or
the tablet during ejection, as well as the compression surfaces of
the two punches (e.g., the upper surface of the lower punch and the
lower surface of the upper punch), are lubricated before the
pre-tabletting material is filled into the die. These surfaces can
be lubricated with the same lubricant(s). They can also be
lubricated with different lubricants. The pre-tabletting material
is preferably in contact with the lubricated surfaces throughout
the duration of compression, and the tablet made therefrom is
preferably in contact with the lubricated die wall and the
lubricated compression surface of the ejection punch during the
course of ejection.
[0063] Lubrication of the internal surface of the die and/or the
compression surfaces of the punches may provide several advantages.
Firstly, lubrication may reduce or eliminate internal fractures in
the tablet, thereby improving the structural stability of the
tablet. This may in turn increase the process yield by reducing
product loss due to capping. Secondly, lubrication of the die wall
and/or compression surfaces may eliminate the necessity of adding
lubricant(s) to the pre-tabletting material, thereby reducing
operation steps. This could also eliminate the dependence of final
tablet quality on the execution of final blend step (for example,
control may be no longer needed for the blending time, order of
powder(s) addition to the blender, speed of the blender, or number
of revolutions). The removal of an extra operation step can
potentially improve manufacturing cycle time, simplify continuous
manufacturing, enhance process throughput, and reduce manufacturing
costs. These improvements in process may also lead to increased
batch size and reduced cost for analytical release testing.
Furthermore, die wall lubrication enables the use of lower
compression pressures to make tablets and, therefore, can reduce
wear and tear of the tabletting machine (including punches and
dies) during each operation cycle.
[0064] Lubricants suitable for the present invention include, but
are not limited to, fatty acids (e.g., stearic acid); fatty acid
salts (e.g., stearic acid salts such as calcium stearate, magnesium
stearate, aluminum stearate, zinc stearate, potassium stearate or
sodium stearate, or fatty acid sodium salts); fatty acid esters
(e.g., stearin or other stearic acid esters); aliphatic alcohol
esters (e.g., sodium stearyl fumarate); lauryl sulfate salts (e.g.,
sodium lauryl sulfate or magnesium lauryl sulfate); waxes (e.g.,
beeswax, carnauba wax, spermaceti, or other animal, plant, mineral,
petroleum or synthetic waxes); fats; talc; hydrogenated oils;
polyethylene glycols; boric acid; adipic acid; fumaric acid;
silicic acid anhydrate or hydrate; hydrated aluminum silicate,
sulfate salts or esters (e.g., sodium sulfate); magnesium oxide;
glycol; sodium benzoate; glyceryl behenate; leucine; starch;
powdered gum arabic; aspartame
(N-.alpha.-L-Aspartyl-L-phenylalanine 1-methyl ester); or any
mixture thereof. The internal surface of the die and/or the
compression surfaces of the punches can be lubricated by one
lubricant, or a combination of two or more lubricants, either with
or without other additives. Preferably, the internal surface of the
die and/or the compression surfaces of the punches are lubricated
with sodium stearyl fumarate, or a combination of sodium stearyl
fumarate and one or more other lubricants. The lubricant(s)
employed in the present invention can be in any suitable physical
forms (e.g., solid, semi-solid, paste, liquid, powder, solution,
atomized, or any mixture thereof).
[0065] Lubricant(s) can be applied to the internal surface of the
die and/or the compression surfaces of the punches by a variety of
means. For instance, lubricant(s) can be manually or automatically
applied to the die wall and/or compression surfaces using brushes.
Lubricant(s) can also be applied to these surfaces by using a
dispensing system, such as those described in U.S. Pat. Nos.
5,609,908, 5,700,492, 6,764,695, and 6,964,779, all of which are
incorporated herein by reference in their entireties. Suitable
lubricant dispensing systems are also commercially available, such
as the PKB 1, PKB 2 and PKB 3 systems manufactured by FETTE GMBH
(Germany).
[0066] A lubricant dispensing system can be readily coupled to a
tablet compression machine such that the step of lubrication is
coordinated with other tabletting steps. See, e.g., the systems
described in U.S. Pat. Nos. 6,764,695 and 6,964,779. Such a
dispensing system becomes an "on-line" or "die-wall" lubrication
unit which allows for continuous tabletting cycles. Each cycle
typically comprises the steps of lubricating the internal surface
of the die and/or the compression surfaces, filling the die with
the pre-tabletting material, compressing the pre-tabletting
material in the die to form a tablet, and ejecting the tablet from
the die. FIG. 1 schematically depicts an exemplary tabletting cycle
which comprises on-line lubrication (Step 1). In Step 1, a
lubricant (or a combination of lubricants) is sprayed through a
spray nozzle(s) onto the internal surface of the die and the
compression surfaces of the punches. In Step 2, the lubricated unit
moves to a filling area (1), where the pre-tabletting material (3)
is filled into the die. In Step 3, the pre-tabletting material is
compressed under pressure by the punches to form a tablet (4). The
tablet is then pushed out of the die by the lower punch in Step 4,
and removed from the equipment by a tablet scraper (2). All of
these steps can be performed on a rotary tablet compression
machine. Additional steps, such as precompression after Step 2 and
before Step 3, can also be included in the cycle.
[0067] The compression pressure in Step 3 (and the precompression
pressure if any) can range, for example, from 10 kN/cm.sup.2 to 50
kN/cm.sup.2. Preferably, the compression pressure is at least 10
kN/cm.sup.2 (or at least 1 ton/cm.sup.2). For instance, the
compression pressure can be at least 15, 16, 17, 18, 19, 20 or more
kN/cm.sup.2. More preferably, the compression pressure is at least
10 kN/cm.sup.2 but no greater than 30 kN/cm.sup.2, such as no
greater than 25 kN/cm.sup.2, 20 kN/cm.sup.2 or 15 kN/cm.sup.2.
Highly preferably, the compression pressure is from 10 kN/cm.sup.2
to 20 kN/cm.sup.2, such as from 10 kN/cm.sup.2 to 15 kN/cm.sup.2 or
from 15 kN/cm.sup.2 to 20 kN/cm.sup.2.
[0068] Tablets compressed in a lubricated die and/or using
lubricated punches often contain significantly less, or no
detectable, internal fractures, as compared to tablets compressed
in an unlubricated die and using unlubricated punches, depending on
factors such as the compression forces, particle sizes, or whether
internal lubrication is used. As used herein, "significantly less"
means that the average number of internal fractures in the tablets
made using lubricated die/punches is at least 25%, preferably at
least 50%, less than the average number of internal fractures in
the tablets made using unlubricated die/punches. Internal fractures
in a tablet can be detected by XMT, as described hereinbelow.
[0069] Any therapeutic agent that is amenable to tablet
formulations can be tabletted according to the present invention.
Non-limiting examples of these therapeutic agents include drugs for
the treatment of infections, cancers, immune disorders,
neurological disorders, neuro-psychiatric disorders, hematopoietic
disorders, endocrine disorders, cardiovascular disorders, liver
disorders, metabolic disorders, inflammation, or pain. Specific
examples of these therapeutic agents include, but are not limited
to, antiviral agents, such as HIV protease inhibitors, HIV reverse
transcriptase inhibitors, HIV integrase inhibitors, HIV fusion
inhibitors, HCV protease inhibitors, and HCV polymerase inhibitors;
antibiotics; anticancer agents, such as chemotherapeutic agents,
alkylating agents, antimetabolites, plant alkaloids, antitumor
antibiotics, hormones, antihormones, kinase inhibitors, and growth
factor receptor inhibitors; or immunomodulators, such as
anti-inflammatory agents, immunosuppressive agents, and
immunostimulatory agents. As used herein, the terms "therapeutic
agent," "active pharmaceutical ingredient" and "active ingredient"
are used interchangeably.
[0070] Preferably, the therapeutic agent(s) tabletted according to
the present invention is not denaturalized or inactivated when
compressed at a pressure of greater than or equal to 1 ton/cm.sup.2
(about 9.8 kN/cm.sup.2) and is not affected by the lubricant(s)
used on the die wall and compression surfaces. As used herein, a
therapeutic agent is denaturalized or inactivated if the agent is
destabilized or dissolved, or when the agent is in a crystal form
the elution of the agent becomes slow because its crystal is
deformed, by the pressure applied at the time of tabletting or by
the friction or heat generated during tabletting. Examples of
therapeutic agents that can be denaturalized or inactivated by high
tabletting pressures are described in U.S. Pat. No. 6,964,779
(e.g., Tables 3-5), the entire content of which is incorporated
herein by reference. A therapeutic agent is affected by a lubricant
(or a lubricated surface) if the agent is colored, decomposed or
deteriorated in its potency upon contact with the lubricant (or the
lubricated surface). Examples of agents that can be affected by
lubricants are illustrated in U.S. Pat. No. 6,764,695, the entire
content of which is also incorporated herein by reference.
[0071] The pre-tabletting material employed in the present
invention can comprise, for example, from 0.1 to 50% by weight of a
therapeutic agent (or a combination of therapeutic agents). For
instance, the pre-tabletting material can comprise from 0.5 to 25%,
preferably from 1 to 20%, by weight of a therapeutic agent (or a
combination of therapeutic agents). Where the pre-tabletting
material includes two or more therapeutic agents, each agent can be
present, for example, from 0.5 to 25%, preferably from 1 to 20%, by
weight of the total pre-tabletting material. Pre-tabletting
materials comprising more than 50%, 60% or 70% by weight of
therapeutic agent(s) can also be used in the present invention.
[0072] In one example, the pre-tabletting material comprises
ritonavir. In another example, the pre-tabletting material
comprises lopinavir. In yet another example, the pre-tabletting
material comprises a combination of ritonavir and lopinavir. In
still another example, the pre-tabletting material comprises a
combination of ritonavir and lopinavir in a weight ratio of 1:4.
Ritonavir and lopinavir are described in U.S. Pat. Nos. 5,541,206
and 5,914,332, respectively, both of which are incorporated herein
by reference in their entireties.
[0073] In a further example, the pre-tabletting material comprises
ritonavir and another therapeutic agent whose pharmacokinetics can
be improved by ritonavir. In still another example, the
pre-tabletting material comprises ritonavir and another therapeutic
agent which is transported by P-glycoprotein.
[0074] The pre-tabletting material employed in the present
invention preferably does not comprise any lubricant, or contains
only an insignificant amount of lubricant(s). As used herein, the
amount of a lubricant or lubricants in a pre-tabletting material is
"insignificant" if the tablet prepared therefrom has no detectable
structural difference from a similarly prepared tablet using an
otherwise identical pre-tabletting material but without the
lubricant or lubricants. In many cases, the pre-tabletting material
does not contain any lubricant, or the total amount of lubricant(s)
in the pre-tabletting material is less than 0.5% by weight of the
pre-tabletting material. More preferably, the total amount of
lubricant(s) in the pre-tabletting material is less than 0.2%,
0.1%, 0.05%, 0.01% or lesser by weight of the pre-tabletting
material.
[0075] The pre-tabletting material employed in the present
invention comprises a pharmaceutically acceptable polymer or a
combination of two or more pharmaceutically acceptable polymers.
The pre-tabletting material can comprise, for example and without
limitation, at least 30% by weight of a pharmaceutically acceptable
polymer or a combination of pharmaceutically acceptable polymers.
For instance, the pre-tabletting material can comprise at least
40%, 50%, 60%, 70% or 80% by weight of a pharmaceutically
acceptable polymer or a combination of pharmaceutically acceptable
polymers. The present invention also contemplates the use of
pre-tabletting materials that contain less than 30% by weight of
pharmaceutically acceptable polymer(s).
[0076] In many embodiments, the pre-tabletting material comprises a
solid dispersion of at least one therapeutic agent in a matrix
comprising at least one pharmaceutically acceptable polymer. The
term "solid dispersion" defines a system in a solid state (as
opposed to a liquid or gaseous state) comprising at least two
components, wherein one component is dispersed throughout the other
component or components. For example, the active ingredient or
combination of active ingredients can be dispersed in a matrix
comprised of a pharmaceutically acceptable hydrophilic polymer or a
combination of pharmaceutically acceptable hydrophilic polymers, or
in a matrix comprised of a pharmaceutically acceptable
water-soluble polymer or a combination of pharmaceutically
acceptable water-soluble polymers. The matrix can also include
other components, such as a pharmaceutically acceptable
surfactant(s), a flow regulator(s), a disintegrant(s), a
plasticizer(s), a stabilizer(s), or a bulking agent(s) or
filler(s). The term "solid dispersion" encompasses systems having
small particles, typically of less than 1 .mu.m in diameter, of one
phase dispersed in another phase. When said dispersion of the
components is such that the system is chemically and physically
uniform or homogenous throughout or consists of one phase (as
defined in thermodynamics), such a solid dispersion will be called
a "solid solution" or a "glassy solution." A glassy solution is a
homogeneous, glassy system in which a solute is dissolved in a
glassy solvent. Glassy solutions and solid solutions of therapeutic
agents are the preferred physical systems employed in the
pre-tabletting material. Glassy solutions and solid solutions do
not contain any significant amounts of active ingredients in their
crystalline or microcrystalline state, as evidenced by thermal
analysis (e.g., differential scanning calorimetry), near-infrared
analysis, or X-ray diffraction/scattering analysis. The present
invention also contemplates a pre-tabletting material comprising
two or more different solid dispersions each of which includes a
different therapeutic agent.
[0077] The pharmaceutically acceptable polymer(s) employed in the
present invention preferably is water-soluble. In some examples,
the water-soluble polymer(s) can have an apparent viscosity, when
dissolved at 20.degree. C. in an aqueous solution at 2% (w/v), of
from 1 to 5000 mPas, preferably of from 1 to 700 mPas, and more
preferably of from 5 to 100 mPas. Crosslinked or other
water-insoluble or poorly water-soluble polymers can also be used,
either alone or in combination with water-soluble polymers.
[0078] Non-limiting examples of pharmaceutically acceptable
water-soluble or hydrophilic polymers suitable for the present
invention include homopolymers or copolymers of N-vinyl lactams,
such as homopolymers or copolymers of N-vinyl pyrrolidone (e.g.,
polyvinylpyrrolidone (PVP), or copolymers of N-vinyl pyrrolidone
and vinyl acetate or vinyl propionate); cellulose esters or
cellulose ethers, such as alkylcelluloses (e.g., methylcellulose or
ethylcellulose), hydroxyalkylcelluloses (e.g.,
hydroxypropylcellulose), hydroxyalkylalkylcelluloses (e.g.,
hydroxypropylmethylcellulose), and cellulose phthalates or
succinates (e.g., cellulose acetate phthalate and
hydroxypropylmethylcellulose phthalate,
hydroxypropylmethylcellulose succinate, or
hydroxypropylmethylcellulose acetate succinate); high molecular
polyalkylene oxides, such as polyethylene oxide, polypropylene
oxide, and copolymers of ethylene oxide and propylene oxide;
polyacrylates or polymethacrylates, such as methacrylic acid/ethyl
acrylate copolymers, methacrylic acid/methyl methacrylate
copolymers, butyl methacrylate/2-dimethylaminoethyl methacrylate
copolymers, poly(hydroxyalkyl acrylates), and poly(hydroxyalkyl
methacrylates); polyacrylamides; vinyl acetate polymers, such as
copolymers of vinyl acetate and crotonic acid, and partially
hydrolyzed polyvinyl acetate (also referred to as partially
saponified "polyvinyl alcohol"); polyvinyl alcohol; oligo- or
polysaccharides, such as carrageenans, galactomannans, and xanthan
gum; polyhydroxyalkylacrylates; polyhydroxyalkyl-methacrylates;
copolymers of methyl methacrylate and acrylic acid; polyethylene
glycols (PEGs); or any mixture thereof.
[0079] In one embodiment, the water-soluble/hydrophilic polymer(s)
employed in the present invention has a glass transition
temperature (Tg) of at least 50.degree. C., such as at least
60.degree. C., 70.degree. C., or 80.degree. C. Preferably, the
water-soluble/hydrophilic polymer(s) has a Tg of from 80.degree. C.
to 180.degree. C. Methods for determining Tg values of organic
polymers are described in "Introduction to Physical Polymer
Science," 2nd Edition by L. H. Sperling, published by John Wiley
& Sons, Inc., 1992. The Tg value can be calculated as the
weighted sum of the Tg values for homopolymers derived from each of
the individual monomers that make up the polymer, i.e.,
Tg=.SIGMA.W.sub.i X.sub.i where W.sub.i is the weight percent of
monomer i in the organic polymer, and X.sub.i is the Tg value for
the homopolymer derived from monomer i. Tg values for homopolymers
may be taken from "Polymer Handbook," 2nd Edition by J. Brandrup
and E. H. Immergut, Editors, published by John Wiley & Sons,
Inc., 1975.
[0080] Water-soluble/hydrophilic polymers having a Tg of at least
50.degree. C. allow for the preparation of solid dispersions that
are mechanically stable and, within ordinary temperature ranges,
sufficiently temperature stable so that the solid dispersions may
be compacted to tablets without, or with only a small amount of,
tabletting aids. Water-soluble/hydrophilic polymers having a Tg of
below 50.degree. C. may also be used.
[0081] The water-soluble/hydrophilic polymer(s) employed in the
present invention preferably exists in an amorphous form, or is
capable of forming an amorphous matrix, at room temperature
(25.degree. C.). Non-limiting examples of these
water-soluble/hydrophilic polymers include homopolymers of
vinylpyrrolidone (e.g., PVP with Fikentscher K values of from 12 to
100, or PVP with Fikentscher K values of from 17 to 30), and
copolymers of 30 to 70% by weight of N-vinylpyrrolidone (VP) and 70
to 30% by weight of vinyl acetate (VA) (e.g., a copolymer of 60% by
weight VP and 40% by weight VA).
[0082] The pre-tabletting material employed in the present
invention (or the solid dispersion comprised therein) can further
include a pharmaceutically acceptable surfactant or a combination
of pharmaceutically acceptable surfactants. The term
"pharmaceutically acceptable surfactant" refers to a
pharmaceutically acceptable non-ionic surfactant.
[0083] In one embodiment, the pre-tabletting material (or the solid
dispersion comprised therein) comprises at least one surfactant
having a hydrophilic lipophilic balance (HLB) value of from 4 to
10, preferably from 7 to 9. The HLB system (Fiedler, H. B.,
Encyclopaedia of Excipients, 5.sup.th ed., Aulendorf:
ECV-Editio-Cantor-Verlag (2002)) attributes numeric values to
surfactants, with lipophilic substances receiving lower HLB values
and hydrophilic substances receiving higher HLB values.
[0084] Surfactants having an HLB value of from 4 to 10 and suitable
for use in the present invention include, but are not limited to,
polyoxyethylene alkyl ethers, e.g. polyoxyethylene(3)lauryl ether,
polyoxyethylene(5)cetyl ether, polyoxyethylene(2)stearyl ether,
polyoxyethylene(5)stearyl ether; polyoxyethylene alkylaryl ethers,
e.g. polyoxyethylene(2)nonylphenyl ether,
polyoxyethylene(3)nonylphenyl ether, polyoxyethylene(4)nonylphenyl
ether, polyoxyethylene(3)octylphenyl ether; polyethylene glycol
fatty acid esters, e.g. PEG-200 monolaurate, PEG-200 dilaurate,
PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate, PEG-300
dioleate; alkylene glycol fatty acid mono esters, e.g. propylene
glycol monolaurate (Lauroglycol.RTM.); sucrose fatty acid esters,
e.g. sucrose monostearate, sucrose distearate, sucrose monolaurate,
sucrose dilaurate; or sorbitan mono fatty acid esters, e.g.,
sorbitan monolaurate (Span.RTM. 20), sorbitan monooleate, sorbitan
monopalmitate (Span.RTM. 40), or sorbitan stearate; or any mixture
thereof. The sorbitan mono fatty acid esters are preferred, with
sorbitan monolaurate and sorbitan monopalmitate being particularly
preferred.
[0085] The pre-tabletting material (or the solid dispersion
comprised therein) can also include other pharmaceutically
acceptable surfactants having an HLB value of below 4 or above 10.
These surfactants can be used either alone or in combination with
surfactants having an HLB value of from 4 or 10. Non-limiting
examples of these surfactants include polyoxyethylene castor oil
derivates, e.g. polyoxyethyleneglycerol triricinoleate or polyoxyl
35 castor oil (Cremophor.RTM. EL, BASF Corp.) or
polyoxyethyleneglycerol oxystearate such as polyethylenglycol 40
hydrogenated castor oil (Cremophor.RTM. RH 40) or polyethylenglycol
60 hydrogenated castor oil (Cremophor.RTM. RH 60); block copolymers
of ethylene oxide and propylene oxide, also known as
polyoxyethylene polyoxypropylene block copolymers or
polyoxyethylene polypropyleneglycol, such as Poloxamer.RTM. 124,
Poloxamer.RTM. 188, Poloxamer.RTM. 237, Poloxamer.RTM. 388,
Poloxamer.RTM. 407 (BASF Wyandotte Corp.); or mono fatty acid
esters of polyoxyethylene(20)sorbitan, e.g.
polyoxyethylene(20)sorbitan monooleate(Tween.RTM. 80),
polyoxyethylene(20)sorbitan monostearate (Tween.RTM. 60),
polyoxyethylene(20)sorbitan monopalmitate (Tween.RTM. 40), and
polyoxyethylene(20)sorbitan monolaurate (Tween.RTM. 20).
[0086] In one embodiment, the pre-tabletting material employed in
the present invention (or the solid dispersion comprised therein)
contains two or more surfactants, where at least 50 wt % of all
surfactants in the pre-tabletting material (or the solid
dispersion) has an HLB value of from 4 to 10. Preferably, at least
60, 70, 80, 90, or more wt % of all surfactants in the
pre-tabletting material (or the solid dispersion) has an HLB value
of from 4 to 10.
[0087] Various techniques can be used to make solid dispersions.
These techniques include, but are not limited to, melt-extrusion,
spray drying, freeze drying, and solvent evaporation. The solid
dispersions thus prepared can be directly compressed to tablets if
they are already in powder forms, or milled or ground to small
particles before being compressed to tablets. Additional
ingredients may also be mixed with the solid dispersions before
grinding and/or tablet compression.
[0088] The melt-extrusion process typically comprises the steps of
preparing a melt which includes the active ingredient(s), the
polymer(s) and optionally the surfactant(s), and cooling the melt
until it solidifies. "Melting" means a transition into a liquid or
rubbery state in which it is possible for one component to get
embedded, preferably homogeneously embedded, in the other component
or components. In many cases, the polymer component(s) will melt
and the other components including the active ingredient(s) and
surfactant(s) will dissolve in the melt thereby forming a solution.
Melting usually involves heating above the softening point of the
polymer(s). The preparation of the melt can take place in a variety
of ways. The mixing of the components can take place before, during
or after the formation of the melt. For example, the components can
be mixed first and then melted or be simultaneously mixed and
melted. The melt can also be homogenized in order to disperse the
active ingredient(s) efficiently. In addition, it may be convenient
first to melt the polymer(s) and then to mix in and homogenize the
active ingredient(s). In one example, all materials except
surfactant(s) are blended and fed into an extruder, while
surfactant is molten externally and pumped in during extrusion.
[0089] In another example, the melt comprises a water-soluble
polymer or a combination of water-soluble polymers, and the melt
temperature is in the range of from 70 to 250.degree. C.,
preferably from 80 to 180.degree. C., and highly preferably from
100 to 140.degree. C.
[0090] In yet another example, the melt comprises a hydrophilic
polymer or a combination of hydrophilic polymers, and the melt
temperature is in the range of from 70 to 250.degree. C.,
preferably from 80 to 180.degree. C., and highly preferably from
100 to 140.degree. C.
[0091] The active ingredient(s) can be employed as such, or as a
solution or dispersion in a suitable solvent such as alcohols,
aliphatic hydrocarbons, esters or, in some cases, liquid carbon
dioxide. The solvent can be removed, e.g. evaporated, upon
preparation of the melt.
[0092] Various additives can also be included in the melt, for
example, flow regulators (e.g., colloidal silica), binders,
lubricants, fillers, disintegrants, plasticizers, colorants, or
stabilizers (e.g., antioxidants, light stabilizers, radical
scavengers, and stabilizers against microbial attack).
[0093] The melting and/or mixing can take place in an apparatus
customary for this purpose. Particularly suitable ones are
extruders or kneaders. Suitable extruders include single screw
extruders, intermeshing screw extruders or multiscrew extruders,
preferably twin screw extruders, which can be corotating or
counterrotating and, optionally, be equipped with kneading disks.
It will be appreciated that the working temperatures will be
determined by the kind of extruder or the kind of configuration
within the extruder that is used. Part of the energy needed to
melt, mix and dissolve the components in the extruder can be
provided by heating elements. However, the friction and shearing of
the material in the extruder may also provide a substantial amount
of energy to the mixture and aid in the formation of a homogeneous
melt of the components.
[0094] The melt can range from thin to pasty to viscous. Shaping of
the extrudate can be conveniently carried out by a calender with
two counter-rotating rollers with mutually matching depressions on
their surface. The extrudate can be cooled and allow to solidify.
The extrudate can also be cut into pieces, either before (hot-cut)
or after solidification (cold-cut).
[0095] The solidified extrusion product can be further milled,
ground or otherwise reduced to granules. Like the solidified
extrudate, each granule comprises a solid dispersion, preferably a
solid solution, of the active ingredient(s) in a matrix comprised
of the polymer(s) and optionally the surfactant(s). These granules
can be directly fed into a die and compacted to a tablet.
Alternatively, these granules can be blended with other active
ingredient(s) and/or additive(s) before die fill and compaction.
These additional additives can be, for example, flow regulators,
disintegrants, and bulking agents (fillers). Disintegrants promote
a rapid disintegration of the tablet in the stomach and keeps the
granules which are liberated separate from one another. Suitable
disintegrants include, but are not limited to, crosslinked polymers
such as crosslinked polyvinyl pyrrolidone and crosslinked sodium
carboxymethylcellulose. Suitable bulking agents (also referred to
as "fillers") can be selected, for example, from lactose, calcium
hydrogenphosphate, microcrystalline cellulose (Avicel.RTM.),
silicates, silicon dioxide, magnesium oxide, talc, potato or corn
starch, isomalt, or polyvinyl alcohol. Suitable flow regulators
include, but are not limited to, highly dispersed silica
(Aerosil.RTM.), and animal or vegetable fats or waxes. Other
additives can also be added before die fill, for example, dyes such
as azo dyes, organic or inorganic pigments such as aluminium oxide
or titanium dioxide, or dyes of natural origin; and stabilizers
such as antioxidants, light stabilizers, radical scavengers, or
stabilizers against microbial attack.
[0096] The extrusion product can also be blended with other active
ingredient(s) and/or additive(s) before being milled or ground to
granules.
[0097] Preferably, the granules made from the extrudates are not
blended with any lubricants before being fed into a die for
compression. More preferably, the granules are directly fed into a
die and compacted to a tablet without being blended with any
additives or other ingredients.
[0098] Spray drying involves breaking up liquid mixtures into small
droplets and rapidly removing solvent from the mixture in a
container (spray drying apparatus) where there is a strong driving
force for evaporation of solvent from the droplets. The strong
driving force for solvent evaporation is often provided by
maintaining the partial pressure of solvent in the spray drying
apparatus well below the vapor pressure of the solvent at the
temperatures of the drying droplets. This may be accomplished by
either (1) maintaining the pressure in the spray drying apparatus
at a partial vacuum; (2) mixing the liquid droplets with a warm
drying gas; or (3) both.
[0099] The spray drying apparatus suitable for the present
invention can be any of the various commercially available
apparatus. Non-limiting examples of specific spray drying devices
include those manufactured by Niro Inc., Buchi Labortechnik AG, and
Spray Drying Systems, Inc. Spray drying processes and spray drying
equipment are described generally in Perry's Chemical Engineers'
Handbook, Sixth Edition (R. H. Perry, D. W. Green, J. O. Maloney,
eds.) McGraw-Hill Book Co. 1984, pages 20-54 to 20-57. More details
on spray drying processes and equipment are reviewed by Marshall,
"Atomization and Spray Drying," 50 Chem. Eng. Prog. Monogr. Series
2 (1954). The contents of these references are incorporated herein
by reference.
[0100] Besides melt extrusion and spray drying and other solid
dispersion technology, the pre-tabletting material can also be
prepared using other methods, such as wet granulation, dry
granulation or fluidized bed granulation as described in E. Rudnic
and J. Schwartz, "Oral Solid Dosage Forms," REMINGTON'S
PHARMACEUTICAL SCIENCE (18th edition, 1990), chapter 89, pp.
1641-1645, the entire content of which is incorporated herein by
reference. All ingredients in the pre-tabletting material
preferably are well granulated and mixed, such that the tablet made
therefrom has an even distribution of the active ingredient(s) and
the amount of the active ingredient(s) in each tablet is about
equal. Where the active ingredient(s), polymer(s), and optionally,
surfactant(s) and/or other additives can form a sufficiently
homogenous mixture by simple mixing, the simple mixture of these
ingredients can be directly used as a pre-tabletting material for
die fill and tablet compression (direct compression).
[0101] Granules of various sizes can be compacted to tablets
according to the present invention. Preferably, the sizes of the
granules in a pre-tabletting material are substantially uniform.
The mean particle size of the granules in a pre-tabletting material
can range, for example, from 10 .mu.m to 1000 .mu.m. For instance,
the mean particle size of the granules can ranges from 50 to 100
.mu.m, from 100 to 200 .mu.m, from 200 to 300 .mu.m, from 300 to
400 .mu.m, from 400 to 500 .mu.m, from 500 to 600 .mu.m, or from
600 to 700 .mu.m. In one embodiment, at least 90% of the granules
in a pre-tabletting material are smaller than 700 .mu.m (or smaller
than 600, 500, 400, 300, 200, or 100 .mu.m). In another embodiment,
at least 90% of the granules in a pre-tabletting material are
greater than 10 .mu.m (or greater than 20, 50, 100, 150, or 200
.mu.m). In still another embodiment, at least 75% of the granules
in a pre-tabletting material have particle sizes of from 10 to 300
.mu.m (or from 100 to 700 .mu.m, or from 30 to 600 .mu.m).
[0102] The particle size distribution can be determined by sieve
analysis or other means as appreciated by those skilled in the art.
An exemplary sieve analysis involves the use of sieves with
different opening sizes. The sieves can be assembled into a column
with the top sieve having the widest openings and each lower sieve
in the column having smaller openings than the one above. The
column can be placed in a mechanical shaker. The shaker shakes the
column for a pre-determined amount of time. After the shaking is
complete, the material on each sieve is weighed. The weight of the
sample of each sieve is then divided by the total weight to give a
percentage retained on each sieve. The mean particle size can be
calculated using Equation 1:
MPS = C 1 - 50 % C 1 - C 2 .times. ( S 2 - S 1 ) + S 1 Equation 1
##EQU00001##
where C.sub.1 is the accumulated percentage of particles just
larger than 50%; C.sub.2 is the accumulated percentage of particles
just smaller than 50%; S.sub.1 is the size of particles which has
an accumulated percentage just larger than 50%, and S.sub.2 is the
size of the particles which have an accumulated percentage just
smaller than 50%.
[0103] Where a pre-tabletting material contains granules of small
sizes and is compressed at a relatively low pressure, the resulting
tablets may contain significantly less or no detectable internal
fractures, even when the compression is carried out in an
unlubricated die and using unlubricated punches. Accordingly, the
present invention features a process of making tablets from a
granular pre-tabletting material, where 90% of the granules in the
pre-tabletting material are smaller than 400 .mu.m, preferably
smaller than 300 .mu.m, highly preferably smaller than 200 .mu.m,
and most preferably smaller than 100 .mu.m. In addition, the
present invention features a process of making tablets from a
granular pre-tabletting material, where the mean particle size of
the granular pre-tabletting material is no greater than 200 .mu.m,
preferably no greater than 150 .mu.m, and more preferably no
greater than 100 .mu.m. These processes comprise the steps of
compressing the pre-tabletting material in a die to form a tablet,
and ejecting the tablet from the die. The internal surface of the
die or the compression surfaces of the punches can be either
lubricated or unlubricated. Preferably, the compression pressure
employed in this process is no more than 30 kN/cm.sup.2, such as no
more than 25, 20 or 15 kN/cm.sup.2.
[0104] In one aspect, the present invention features the use of a
pre-tabletting material which comprises a solid dispersion of at
least one therapeutic agent in a matrix, wherein said at least one
therapeutic agent comprises (1) ritonavir or (2) ritonavir and
another therapeutic agent (e.g., lopinavir or a therapeutic agent
which is metabolized by cytochrome P450 oxidase or transported by
P-glycoprotein), and said matrix comprises one or more
pharmaceutically acceptable hydrophilic polymers (or one or more
pharmaceutically acceptable water-soluble polymers). Preferably,
the pre-tabletting material does not include (1) any therapeutic
agent that is denaturalized or inactivated when compressed at a
pressure of greater than or equal to 1 ton/cm.sup.2, (2) any low
molecule active ingredient the elution of which is delayed when
compressed at a pressure of greater than or equal to 1
ton/cm.sup.2, or (3) any therapeutic agent that is affected by the
lubricant(s) used on the internal surface of the die and/or the
compression surfaces.
[0105] The pre-tabletting material employed in this aspect of the
invention can comprise, for example, at least 50% by weight of said
one or more water-soluble/hydrophilic polymers. Preferably, the
pre-tabletting material comprises at least 60%, 65% or 70% by
weight of said one or more water-soluble/hydrophilic polymers. Each
of said one or more water-soluble/hydrophilic polymers preferably
has a Tg of at least 50.degree. C. More preferably, each of said
one or more water-soluble/hydrophilic polymers has a Tg of from 80
to 180.degree. C. Water-soluble/hydrophilic polymers with a Tg of
below 50.degree. C. and/or water-insoluble polymers can also be
included in the matrix.
[0106] The matrix can further include one or more pharmaceutically
acceptable surfactants. The pre-tabletting material can comprise,
for example, from 1 to 30% by weight of said one or more
surfactants. Preferably, the pre-tabletting material comprises from
2 to 20% by weight of said one or more surfactants. Each of said
one or more surfactants preferably has an HLB value of from 4 to
10. Surfactants having an HLB value of below 4 or above 10 may also
be used. Where the pre-tabletting material comprises two or more
surfactants, preferably at least 50 wt % of all surfactants, based
on the total weight of all surfactants in the pre-tabletting
material, have an HLB value(s) of from 4 to 10.
[0107] Any water-soluble/hydrophilic polymer and surfactant
described hereinabove may be used in this aspect of the invention.
Preferred water-soluble/hydrophilic polymers include homopolymers
or copolymers of N-vinyl pyrrolidone, such as copovidone. Preferred
surfactants include sorbitan mono fatty acid esters, such as
sorbitan monolaurate. The matrix employed in this aspect of the
invention can also include other additive(s), such as colloidal
silicon dioxide.
[0108] The pre-tabletting material employed in this aspect of the
invention preferably is a granular or powdery material which
comprises particles, each particle including a solid dispersion of
said at least one therapeutic agent in said matrix. The solid
dispersion preferably is a solid solution or a glassy solution. The
matrix preferably is an amorphous matrix in which said at least one
therapeutic agent (e.g., ritonavir, or ritonavir and another
therapeutic agent) is molecularly dispersed. More preferably, the
pre-tabletting material is prepared by melt extrusion. In one
example, the melt extrusion includes the steps of (1) preparing a
melt comprising said at least one therapeutic agent, said one or
more water-soluble/hydrophilic polymers and, optionally, said one
or more surfactants, (2) solidify said melt and (3) milling or
grinding said melt to provide the pre-tabletting material. Spray
drying and other methods for the preparation of solid dispersions
can also be used to prepare the pre-tabletting material of this
aspect of the invention.
[0109] The pre-tabletting material employed in this aspect of the
invention can comprise, for example, at least 1, 5, 10, 15 or 20%
by weight of ritonavir. In many cases, the pre-tabletting material
comprises from 1 to 50% by weight of ritonavir. Preferably, the
pre-tabletting material comprises from 1 to 20% by weight of
ritonavir. In one example, the pre-tabletting material comprises,
relative to the total weight of the pre-tabletting material, from 3
to 30% by weight of ritonavir or ritonavir and another therapeutic
agent, from 2 to 20% by weight of said one or more surfactants, and
at least 50% by weight of said one or more
water-soluble/hydrophilic polymers, where each said surfactant
preferably has an HLB value of from 4 to 10 and each said polymer
preferably has a Tg of at least 50.degree. C. Specific examples of
pre-tabletting materials suitable for this aspect of the invention
can be found in Tables 1 and 2 and Examples 1-7 of U.S. Patent
Application Publication No. 20050084529.
[0110] The tablet made according to this aspect of the invention
preferably shows a dose-adjusted AUC of ritonavir plasma
concentration in dogs, under non-fasting conditions, of at least 5
.mu.gh/ml/100 mg, such as at least 9, 10, 15 or 20 gh/ml/100
mg.
[0111] The tablet thus made is often characterized by an excellent
stability, and exhibits high resistance against recrystallization
or decomposition of ritonavir and/or other active ingredient(s). In
many cases, upon storage for 6 weeks at 40.degree. C. and 75%
humidity (e.g., when kept in high density polyethylene(HDPE)
bottles without desiccant), the tablet contains at least 98% of the
initial content of ritonavir and other active ingredient(s) (as
evidenced by HPLC analysis) and does not exhibit any sign of
crystallinity (as evidenced by near infrared spectroscopy,
differential scanning calorimetry, or wide-angle x-ray scattering
analysis).
[0112] In one embodiment of this aspect of the invention, the
pre-tabletting material comprises a solid dispersion of ritonavir
and lopinavir. The pre-tabletting material can comprise, for
example, at least 5, 10, 15, 20, 25, 30, 35 or 40% by weight of
lopinavir. Preferably, the pre-tabletting material comprises from 5
to 40% by weight of lopinavir. In one example, the pre-tabletting
material comprises from 1 to 10% by weight of ritonavir and from 4
to 40% by weight of lopinavir. The ratio of ritonavir over
lopinavir may range, for example, from 1:1 to 1:8, and the
preferred ritonavir over lopinavir ratio is 1:4. Non-limiting
examples of ritonavir/lopinavir combination include 2% ritonavir
and 8% lopinavir, 4% ritonavir and 16% lopinavir, or 8% ritonavir
and 32% lopinavir.
[0113] Preferably, the tablet made from this pre-tabletting
material shows a dose-adjusted AUC of ritonavir plasma
concentration in dogs, under non-fasting conditions, of at least 5
gh/ml/100 mg (e.g., at least 9, 10, 15 or 20 .mu.gh/ml/100 mg), and
a dose-adjusted AUC of lopinavir plasma concentration in dogs,
under non-fasting conditions, of at least 15 .mu.gh/ml/100 mg
(e.g., at least 20, 22.5, 25, 30, 35, 40, 45 or 50 .mu.gh/ml/100
mg). For instance, the tablet can have a dose-adjusted AUC of
ritonavir plasma concentration of at least 5 .mu.gh/ml/100 mg and a
dose-adjusted AUC of lopinavir plasma concentration of at least 15
.mu.gh/ml/100 mg; or a dose-adjusted AUC of ritonavir plasma
concentration of at least 9 .mu.gh/ml/100 mg and a dose-adjusted
AUC of lopinavir plasma concentration of at least 20 .mu.gh/ml/100
mg (preferably at least 22.5 .mu.gh/ml/100 mg, most preferred at
least 35 gh/ml/100 mg); or a dose-adjusted AUC of ritonavir plasma
concentration of at least 10 .mu.gh/ml/100 mg and a dose-adjusted
AUC of lopinavir plasma concentration of at least 40 .mu.gh/ml/100
mg, where all AUCs are measured in dogs under non-fasting
conditions.
[0114] As used herein, "AUC" refers to the area under the plasma
concentration time curve (AUC) from 0 to 24 hours, where the tablet
at issue has been administered orally to dogs (beagle) under
non-fasting conditions. "Non-fasting condition" means that the dogs
receive a nutritionally balanced daily ration during the pre-test
period and the whole test period. The AUC has units of
concentration times time. Once the experimental concentration-time
points have been determined, the AUC may conveniently be
calculated, e.g. by a computer program or by the trapezoidal
method. All AUC data are dose adjusted to the 100 mg dose level.
For the purposes herein, the AUC is preferably determined within a
dose range where the AUC increases proportionally with dose.
Protocol for the oral bioavailability studies in beagle dogs and
the AUC calculations are described in U.S. Patent Application
Publication No. 20050084529, the entire content of which is
incorporated herein by reference.
[0115] In another embodiment of this aspect of the invention, the
pre-tabletting material comprises a solid dispersion of ritonavir
and another therapeutic agent whose pharmacokinetics can be
improved by ritonavir. Ritonavir has been shown to be capable of
inhibiting cytochrome P450 oxidase, such as the P450 3A4 isozyme
(CYP3A4). As a result, co-administration of ritonavir with a drug
that is metabolized by cytochrome P450 oxidase (e.g., CYP3A4) may
enhance the pharmacokinetics of the drug. See U.S. Pat. No.
6,037,157, which is incorporated herein by reference in its
entirety. As used herein, improved pharmacokinetics refers to
improved C.sub.max (the maximum plasma level), T.sub.max (time to
maximum plasma level), AUC or plasma half-life of the drug, or
improved level of the drug in blood, liver or another tissue.
Non-limiting examples of drugs whose pharmacokinetics can be
improved by ritonavir are described in U.S. Pat. No. 6,037,157. In
general, the amount of ritonavir in the tablet is sufficient to
boost the in vivo pharmacokinetics of the co-formulated
drug(s).
[0116] In yet another embodiment of this aspect of the invention,
the pre-tabletting material comprises a solid dispersion of
ritonavir and another therapeutic agent which is metabolized by
cytochrome P450 oxidase, such as CYP3A4. Examples of these
therapeutic agents include, but are not limited to,
immunomodulators (e.g., cyclosporine or FK-506), anti-cancer or
chemotherapeutic agents (e.g., taxol or taxotere), antibiotics
(e.g., clarithromycin, erythromycin, or telithromycin), antivirals
(e.g., indinavir, atazanavir, lopinavir, nelfinavir,
saquinavir,
##STR00001##
(compound VX-950, Vertex Pharmaceuticals Inc.),
##STR00002##
(compound SCH503034, Schering-Plough Co.),
##STR00003##
(compound GS9137, Gilead Sciences, Inc., Foster City, Calif.)),
antihistamines (e.g., astemizole, chlorpheniramine, or
terfenidine), calcium channel blockers (e.g., amlodipine,
diltiazem, felodipine, lercanidipine, nifedipine, nisoldipine,
nitrendipine, or verapamil), beta blockers (e.g., carvedilol,
S-metoprolol, propafenone, or timolol), antidepressants (e.g.,
amitriptyline, clomipramine, desipramine, imipramine, or
paroxetine), or prodrugs thereof.
[0117] In still another embodiment of this aspect of the invention,
the pre-tabletting material comprises a solid dispersion of
ritonavir and another therapeutic agent which is transported by
P-glycoprotein. P-glycoprotein, also known as ATP-binding cassette
sub-family B member 1, is an ATP-dependent efflux pump with broad
substrate specificity. P-glycoprotein is expressed in a variety of
cells such as those lining the intestine and those comprising the
blood-tissue barriers. It is believed that P-glycoprotein functions
as a membrane transporter and is capable of pumping out various
drugs from cytoplasm, thereby reducing the bioavailability of these
drugs. P-glycoprotein is also believed to be involved in multidrug
resistance. Ritonavir can inhibit the activity of P-glycoprotein.
Therefore, co-administration of ritonavir with a drug that is a
substrate of P-glycoprotein can improve the absorption or
bioavailability of the drug. Drugs that can be transported by
P-glycoprotein include, but are not limited to, numerous HIV
protease and reverse transcriptase inhibitors, chemotherapeutic
agents, steroids, xenobiotic, and immunosuppressive agents.
[0118] The present invention also contemplates the use of a
pre-tabletting material which comprises a solid dispersion of
ritonavir and a solid dispersion of another therapeutic agent. The
solid dispersion of ritonavir and the solid dispersion of the other
therapeutic agent can be prepared separately and then combined to
provide the pre-tabletting material. The solid dispersion of
ritonavir and the solid dispersion of the other therapeutic agent
can be prepared using the same polymer(s) and/or additives, or
using different polymer(s) and/or additives.
[0119] In another aspect, the present invention features a
pre-tabletting material which comprises a solid dispersion of at
least one therapeutic agent in a matrix, where said at least one
therapeutic agent comprises an HIV or HCV protease inhibitor, and
said matrix comprises one or more pharmaceutically acceptable
hydrophilic polymers (or one or more pharmaceutically acceptable
water-soluble polymers) and, optionally, one or more
pharmaceutically acceptable surfactants. In one embodiment, the
pre-tabletting material comprises from 5 to 30% (preferably from 10
to 25%) by weight of the total pre-tabletting material of an HIV or
HCV protease inhibitor (or a combination of HIV or HCV protease
inhibitors), at least 50% (preferably from 50 to 85%, and more
preferably from 60 to 80%) by weight of the total pre-tabletting
material of said one or more water-soluble/hydrophilic polymers,
from 2 to 20% (preferably from 3 to 15%) by weight of the total
pre-tabletting material of said one or more surfactants, and from 0
to 15% by weight of the total pre-tabletting material of one or
more other additives.
[0120] HIV protease inhibitors suitable for use in the present
invention include, but are not limited to, ritonavir, lopinavir,
indinavir, saquinavir,
5(S)-Boc-amino-4(S)-hydroxy-6-phenyl-2(R)phenylmethylhexanoyl-(L)-Val-(L)-
-Phe-morpholin-4-ylamide,
1-Naphthoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-butanoy-
l-1,3-thiazolidine-4t-butylamide,
5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-bu-
tanoyl-1,3-thiazolidine-4-tbutylamide, [1S-[1R--(R-),2S*])--N.sup.1
[3-[[[(1,1-dimethylethyl)amino]carbonyl](2-methylpropyl)amino]-2hydroxy-1-
-(phenylmethyl)propyl]-2-[(2-quinolinylcarbonyl)amino]-butanediamide,
amprenavir (VX-478), DMP-323, DMP-450, AG1343 (nelfinavir),
atazanavir (BMS 232,632), tipranavir, palinavir, TMC-114,
RO033-4649, fosamprenavir (GW433908), P-1946, BMS186,318,
SC-55389a, BILA 1096 BS, and U-140690. HCV protease inhibitors
suitable for use in the present invention include, but are not
limited to, VX-950, compound SCH503034, ITMN-191/R7227, and
TMC435350.
[0121] The tablets made according to the present invention
preferably contain significantly less internal fractures, as
compared to the tablets made from the same pre-tabletting material
but using an unlubricated die and punches. More preferably, the
tablets made according to the present invention do not contain any
internal fracture that is detectable by XMT.
[0122] The present invention also features a tablet comprising a
solid dispersion of at least one therapeutic agent in an
above-described matrix, wherein the tablet does not contain any
lubricants, or contains only an insignificant amount of
lubricant(s), and wherein the tablet does not contain (1) any
therapeutic agent that is denaturalized or inactivated when
compressed at a pressure of greater than or equal to 1
ton/cm.sup.2, (2) any low molecule active ingredient the elution of
which is delayed when compressed at a pressure of greater than or
equal to 1 ton/cm.sup.2, or (3) any therapeutic agent that is
affected by the lubricant(s) comprised in the tablet (if any) or
any lubricant used on the die wall and/or compression surfaces. As
used herein, an ingredient in a tablet is in an "insignificant"
amount if the tablet having the ingredient has no detectable
structural difference from an otherwise identically prepared tablet
except that the latter tablet does not have the ingredient. Any
therapeutic agent or agents described herein can be formulated in
such a tablet.
[0123] In addition, the present invention features a tablet
comprising a solid dispersion of at least one therapeutic agent in
an above-described matrix, wherein the tablet does not contain any
lubricants, or the total amount of lubricant(s) in the tablet is
less than 0.5% by weight of the tablet, and wherein the tablet does
not contain (1) any therapeutic agent that is denaturalized or
inactivated when compressed at a pressure of greater than or equal
to 1 ton/cm.sup.2, (2) any low molecule active ingredient whose
elution is delayed when compressed at a pressure of greater than or
equal to 1 ton/cm.sup.2, or (3) any therapeutic agent that is
affected by the lubricant(s) comprised in the tablet (if any) or
any lubricant used on the die wall and/or compression surfaces. In
some cases, the total amount of lubricant(s) in the tablet is less
than 0.25% by weight of the tablet. Preferably, the total amount of
lubricant(s) in the tablet is less than or 0.1%, 0.05%, 0.01% or
lesser by weight of the tablet. Any therapeutic agent or agents
described herein can be formulated in such a tablet.
[0124] In order to facilitate the intake of a tablet by a mammal,
it is advantageous to give the tablet an appropriate shape. Large
tablets that can be swallowed comfortably are therefore preferably
elongated rather than round in shape.
[0125] A film coat on the tablet can further contribute to the ease
with which it can be swallowed. A film coat can also improve taste
and provide an elegant appearance. If desired, the film-coat may be
an enteric coat. The film-coat usually includes a polymeric
film-forming material such as hydroxypropyl methylcellulose,
hydroxypropylcellulose, and/or acrylate or methacrylate copolymers.
Besides a film-forming polymer, the film-coat may further comprise
a plasticizer, e.g. polyethylene glycol, a surfactant, e.g. a
Tween.RTM. type, and optionally a pigment, e.g. titanium dioxide or
iron oxides. The film-coating may also comprise talc as
anti-adhesive. The film coat usually accounts for less than 5% by
weight of the dosage form (unless the film coat is a control
release coat or an active coat).
[0126] The exact dose and frequency of administration depends on
the particular condition being treated, the age, weight and general
physical condition of the particular patient as well as other
medication the individual may be taking.
[0127] The presence of the lubricant layer(s) on a tablet can be
detected using the Secondary Ion Mass Spectrometry (SIMS) or other
suitable techniques. SIMS is the mass spectrometry of ionized
particles which are emitted from the surface when energetic primary
particles bombard the surface. The pulsed primary ions with the
energy of 1-25 keV, typically liquid metal ions such as Ga.sup.+,
Cs.sup.+ and O.sup.-, can be used to bombard the sample surface,
causing the secondary elemental or cluster ions to emit from the
surface. The secondary ions are then electrostatically accelerated
into a field-free drift region. The ion with lower mass has higher
flight velocity than one with higher mass. Thus they will reach the
secondary-ion detector earlier. As a result, the mass separation is
obtained in the flight time t from the sample to the detector. A
variety of mass ions are recorded by the detector with the time
sequence to give the SIMS spectrum.
[0128] It should be understood that the above-described embodiments
and the following examples are given by way of illustration, not
limitation. Various changes and modifications within the scope of
the present invention will become apparent to those skilled in the
art from the present description.
Example 1
[0129] Compression of tablets containing a high percentage of
polymeric excipients presents a significant challenge. As
demonstrated below, polymers may have significant volume expansion
after compaction, leading to the propagation of internal
micro-cracks and large shear planes. Polymers can also exhibit high
wall friction. Without limiting the present invention to any
particular theory, it is postulated that the combination of these
effects may lead to structural failure during tablet compression or
upon storage.
[0130] When compared to normal excipients used in the manufacture
of tablets, polymers exhibit significantly high elastic recovery.
XMT images indicated that internal shear failure planes developed
inside the polymer-based tablet. Furthermore, with an increase in
compression force, the failure planes became aligned perpendicular
to the applied force. This realignment of shear failure planes may
significantly produce failure in process. Moreover, particle size
distribution can also significantly alter the formation of internal
shear failure planes inside the tablet. Fine particles showed a
reduction of shear failure planes compared to coarse particles.
[0131] A strong dependence between the internal failure planes and
the processing variables like particle size distribution and
compaction load is also demonstrated below. With an increase in
applied force during compaction, the internal shear failure planes
realign. This acts as a precursor to capping or delamination. The
combination of compaction simulation and XMT provides an excellent
tool to assess tendency towards failure in process.
[0132] Internal structural flaws often remain undetected by visual
inspection. The flaws may result in capping during post compression
processing. The present invention analyzed the internal structure
of a tablet in a non-destructive manner. X-ray microtomography,
capable of looking at the internal structure of the tablets, was
used to understand the structural inequalities inside the tablets
thereby enabling modification of the operating parameters to
eliminate capping incidence during manufacturing. The equipment
described hereinbelow has a resolution of 2 microns and can
accommodate a sample size of up to 2 cm. An analysis that links the
operating parameters in manufacturing (using a compaction
simulator) to the internal structural flaws enables process
optimization so that capping of the tablets can be minimized or
prevented.
Procedures
[0133] Tablets were compressed on a Presster compaction simulator
(Metropolitan Computing Corp., New Jersey, USA). A Skyscan X-ray
micro-tomograph (model Skyscan 1172; SKYSCAN, Belgium) was used to
generate the scans.
[0134] The Presster simulator is a linear compaction simulator that
imitates the rotary compaction presses. A hopper holds the powder,
which is discharged into the die just before engagement. The die
and the punches move on a linear rail and the ramps located
underneath the bottom punch raises the bottom punch during
compaction and ejection. It has two wheels that engage on the top
punch to create the necessary compressing forces. The wheels can be
lowered or raised manually or electronically to increase or
decrease the compaction force. By changing the linear velocity of
the die table movement, the dwell time can be varied. This system
is versatile in replicating the rotary presses. For the study
described herein, the operating load for the pre-compaction was set
at 9 kN. The compaction force was varied from 36 to 42 to 48
kN.
[0135] The extrudate was prepared according to Examples 2 and 3 of
U.S. Patent Application Publication No. 20050084529 except that
Span 20 was added during extrusion. The entire content of U.S.
Patent Application Publication No. 20050084529 is incorporated
herein by reference. The compositions of the extrudate and the
post-extrusion blend are described in Table 1.
TABLE-US-00001 TABLE 1 Compositions of Target Milled Extrudate and
Post-Extrusion Blend Ingredients Parts by Weight Target Milled
Extrudate Lopinavir 200 Ritonavir 50 Copovidone K28 (Kollidon VA
64; BASF) 853.8 Sorbitan monolaurate 83.9 Colloidal silicon dioxide
12.0 Additional Ingredients in Post-Extrusion Blend Sodium stearyl
fumarate 12.3 Colloidal silicon dioxide 8.0
[0136] The extrudate were milled to the desired particle size
distribution. The particle size distribution of the milled
extrudate (hereinafter the target milled extrudate) is shown in
FIG. 2A. The fine extrudate and the coarse extrudate were separated
by sieving the target milled extrudate using 170 micron mesh (the
upper cut being the coarse), and their particle size distributions
are depicted in FIGS. 2B and 2C, respectively.
[0137] Apart from the milled extrudate, Avicel.RTM. PH101
(microcrystalline cellulose; FMC BioPolymer, Philadelphia, Pa.) and
fast flow lactose were used for the analysis. Avicel.RTM. PH101 has
been historically considered to be a material that is easy to
compress due to plasticity, whereas pure lactose is brittle and is
very challenging to tabletting process.
On-Line Lubrication System
[0138] The on-line lubrication unit Fette PKB 2 (FETTE GMBH,
Hamburg, Germany) was used to lubricate die wall. The system
includes a loss-in-weight feeder enabling for constant flow of the
lubricant(s) (e.g., sodium stearyl fumarate), a slit nozzle to
atomize and spray the lubricant(s) onto the surfaces of the press
chamber prior to filling of the die with the pre-tabletting powder,
and a suction unit to remove excess lubricant(s) from rotor and die
to avoid uncontrollable dust exposure during the compression
process. The material flow from feeder to nozzle was conducted or
controlled by pressurized air. Both components were linked by
flexible tubing.
[0139] The spray rate can be adjusted, and the actual value was
displayed. For common compression processes the feeding rate was in
the range of 100-800 grams per hour, depending on the
characteristics of the to-be-compressed powder blend and other
factors. Start and stop of the feeding cycle can be controlled
manually or, if connected to a Fette control terminal,
automatically in-line with the start/stop signal of the tablet
press. Charging of the lubricant container which holds up to 3 kg
of lubricant is a manual process.
Presster Compaction Simulations
[0140] During the compaction simulation, one significant
observation was the high elastic recovery of the tablets. This was
observed from the force versus displacement graph for the material
at various compaction forces for the lubricated blend (the target
milled extrudate blended with sodium stearyl fumarate and colloidal
silicon dioxide, as showed in Table 1) and the unlubricated blend.
Various reasons may be attributed to this behavior. The application
of high compaction force may be one factor that can contribute to
this observation as the material could have passed through its
maximum plastic deformation. When the material is over compressed,
the tendency for the top punch to bounce back might also be the
reason for the high value of elastic recovery. The design of the
punches could also contribute to the high elastic recovery. In
addition, it was observed that the elastic recoveries are different
between the lubricated and unlubricated blends, whereas there was
no significant difference between the elastic recoveries of the
over lubricated (i.e., blended with the same amount of lubricant(s)
as in the lubricated blend but the blending process took an
extended period of time) and the lubricated blends. For the
unlubricated tablets, an elastic recovery of 14.2 was observed
whereas for Avicel and lactose, these values were 7 and 6.4,
respectively. This observation of high elastic recovery of the
unlubricated blend was an indication of propensity to cap in
process.
[0141] Using the density of the material and the thickness changes
during the compaction, the Heckel plots were constructed. One
observation from the Heckel plot was the lack of major deformation
in the initial stages of compaction for the milled extrudate. The
initial variation in the slope, which is attributed to this
rearrangement, was mostly absent in the polymer-containing
formulations that were tested. This might be due to either large
deformation of individual particles attributed to elasticity or due
to high inter-particle friction that prevents slip between
particles. Even at this high compression, fast flow lactose and
Avicel.RTM. PH101 showed these deformations.
[0142] The high elasticity of the material was reconfirmed from the
Heckel plot. The deviation from the horizontal for different
materials is an indication of this elasticity. Even Avicel.RTM.
PH100 showed this high deformation and hence it can be concluded
that the operating loads need to be lowered to avoid this high
elasticity.
[0143] From the inverse of the slope of initial deformation part of
the Heckel plot, the mean yield pressure was obtained for different
materials (FIG. 3). The unlubricated blend when compressed with die
wall lubricated ("Unlubed Meltrex with die wall lubing") appeared
to be better than the lubricated blend without die wall lubrication
("Target blend") and even Avicel.RTM. PH101 in terms of
compressibility. The unlubricated blend without die wall
lubrication ("Unlubed Meltrex") was worse than fast flow lactose
with die wall lubrication ("Lactose with wall lubing").
[0144] The above analysis demonstrated the presence of large
elastic deformation towards the capping of polymer-based
tablets.
X-Ray Microtomography
[0145] X-ray images of the tablets made from the lubricated blend
without die wall lubrication showed significantly deep internal
cracks extending into the material matrix. The tablets showed
internal failure planes extending from the side of the tablet. This
means that the tablets had structurally failed even though
optically they appear to be perfect. A large number of micro cracks
were also observed for these materials. It appears that the large
cracks have a tendency to form first and then orient perpendicular
to the applied force with increasing applied compaction force. The
micro cracks appear to undergo a reorientation inside the material
matrix during ejection.
[0146] FIGS. 4A, 4B and 4C illustrate the X-ray images of exemplary
tablets made of the target milled extrudate and compressed in an
unlubricated die at 36 kN, 42 kN and 48 kN, respectively. FIGS. 4D
and 4E show the X-ray images of representative tablets made of the
target milled extrudate and compressed in a lubricated die at 42 kN
and 48 kN, respectively.
Effect of Particle Size Distribution
[0147] It was observed that particle size distribution has a
significant impact on tablet internal structure. XMT images showed
that tablets compacted from the fine extrudate at 36 kN had
significantly less internal fractures and micro cracks and, in many
instances, did not have any detectable internal fractures or micro
cracks (FIG. 5A without die wall lubrication; FIG. 5B with die wall
lubrication). The Heckel plot during compaction showed that the
fine extrudate underwent reorganization in the initial stages of
compaction, whereas the target milled extrudate and the coarse
extrudate did not show this behavior. This reorganization of
particles during the initial phase of compaction may explain the
significantly reduced internal structural failure of the fine
extrudate. Another significant observation was that the XMT images
between the fine extrudate compressed in unlubricated die (FIG. 5A)
and the fine extrudate compressed in lubricated die (FIG. 5B) did
not show significant difference in internal fractures. For the fine
extrudate, the shear failure planes started to appear at 42 kN main
compression force without die wall lubrication (FIG. 6A; compared
to FIG. 6B with die wall lubrication) and increased in depth when
the main compression force was increased to 48 kN (FIG. 7A without
die wall lubrication; FIG. 7B with die wall lubrication).
[0148] Shear failure planes were also observed for tablets made of
coarse particles without die wall lubrication. For instance, FIG.
8A shows an exemplary tablet made of coarse particles and
compressed in an unlubricated die at 42 kN. A large amount of micro
cracks were observed for these coarse particles. This indicated
that particle size distribution has a significant influence on how
the compact behaves during compression.
Effect of Die Wall Lubrication
[0149] As demonstrated in FIGS. 4B vs. 4D, 4C vs. 4E, 6A vs. 6B, 7A
vs. 7B, and 8A vs. 8B, tables compacted with lubricated die wall
(FIGS. 4D, 4E, 6B, 7B, and 8B) showed significantly less internal
fractures or micro cracks than tablets compacted without die wall
lubrication (FIGS. 4B, 4C, 6A, 7A, and 8A, respectively). The
effect of die wall lubrication on internal fractures was observed
for both the fine extrudate and the coarse extrudate.
[0150] FIG. 9 depicts the XMT images of a representative tablet
made of the coarse extrudate and compressed at 48 kN with die wall
lubrication, demonstrating a significantly improved internal
structure.
CONCLUSIONS
[0151] Without limiting the present invention to any particular
theory, it is believed that polymers have relatively higher
friction with stainless steel and tend to expand after compaction.
The elastic recovery of the tablet can lead to internal microcracks
due to polymer expansion above hydrostatic state. Moreover, due to
the wall friction, shear failure zones are developed, separating
the free and sheared surfaces and leading to capping.
[0152] The compaction of the target milled, fine and coarse
extrudates were studied using an MCC Presster compaction simulator
and X-ray microtomography. It was observed that the target milled
extrudate has a higher elastic recovery than traditional
Avicel-Lactose based tablets. The flexibility of the material led
to large shear failure zones that created tablet failure.
[0153] The mean yield pressure values obtained by the Heckel
analysis indicated that the target milled extrudate was challenging
to compress without the lubricant. When the wall friction was
reduced using die wall lubrication, compression was facilitated.
X-ray microtomography was also used to image the inside of the
tablets nondestructively and it was observed that tablets made with
the coarse extrudate and the target milled extrudate showed a
tendency to develop micro cracks inside the tablet core. These
cracks can grow and develop into failure planes. Moreover, it was
observed that the cracks underwent a reorientation with increased
compaction load. They tended to align perpendicular to the normal
applied load at high compaction loads. This observation provides an
explanation to material failure in process and can be used as a
tool for process optimization. This tendency was observed for
tablets that showed capping during demonstration runs.
[0154] In all tested cases the shear failure planes disappeared or
significantly reduced when die wall lubrication was used. Hence, by
lubricating die walls, the structural integrity of the tablets can
be improved. The use of the die wall lubrication can lead to
processability improvement, thereby eliminating or reducing capping
ore delamination in process. Particle size distribution also showed
an important role in the formation of micro cracks. The use of more
fine particles during compaction can therefore significantly
improve the structural integrity of the tablets during
processing.
Example 2
[0155] A lubricant feed rate--ejection force profile, and
subsequently a compression force--hardness profile at a constant
lubricant feed rate, were recorded. Compared to the process without
die wall lubrication, the tablet hardness specification could be
met at lower compression forces. The tolerability of the ejection
force to slight variations of the lubricant feed rate was
acceptable with respect to consistent ejection forces, showing the
robustness of the process.
[0156] Lubricant was removed from the pre-tabletting powder blend,
and the surfaces of the press chamber were layered with lubricant.
These were achieved by using a lubricant spraying system (Fette PKB
2) which provided a constant flow of magnesium stearate, sodium
stearyl fumarate or other suitable lubricants. The lubricant was
sprayed into the press chamber by means of pressurized air.
Afterwards excess material was removed and the press chamber was
filled with non-lubricated pre-tabletting powder for
compression.
[0157] The milled extrudate was prepared as described in Example 1
and comprised 16.67% lopinavir, 4.17% ritonavir, 71.16% copovidone
K28, 7% Span 20, and 1% silicon dioxide. The milled extrudate was
compressed, and no precursory blending with additives like
lubricants or glidants was performed. For every extrudate a
lubricant feed rate--ejection force profile, as well as a
compression force--hardness profile at an appropriate feed rate,
were recorded. The lubricant used was sodium stearyl fumarate.
Compression runs were conducted on a Fette 1200 (FETTE GMBH,
Hamburg, Germany), which was coupled with Fette PKB 2 to provide
on-line lubrication of die wall. Main compression force was varied
from 14.8 to 41.9 kN. During compression, rotary speed,
fill-o-matic speed, main compression force, ejection force and
lubricant feed rate were recorded. From all trials a sample was
taken and tested for tablet hardness and friability.
[0158] With die wall lubrication, the milled extrudate can be
easily compressed with compression forces of 21 kN or above. When
the milled extrudate was blended with 1% sodium stearyl fumarate
and 0.66% silicon dioxide, the blend had to be compressed (without
die wall lubrication) at 30-40 kN to achieve a tablet hardness in a
comparable range. It was also observed that sodium stearyl fumarate
concentrations from 0.05% to 0.3% had a significant impact on
tablet hardness if blended with the extrudates prior to compression
but without die wall lubrication. With on-line die wall
lubrication, tablet hardness was not affected as the core of the
tablet is nearly lubricant-free. The ejection forces seemed to be
quite constant in a relatively small range with respect to the
lubricant feed rate.
[0159] The on-line lubrication process may offer several advantages
compared to the processes where milled extrudates are blended with
lubricants and then compressed in unlubricated die. These
advantages include significantly shorter process flow (e.g.,
blending for lubricant can be removed), no scaling-up of blending
process, reduced number of process parameters and variables,
facilitating a continuous manufacturing process, and enabling for
pure tablet cores without influence of compression additives.
[0160] The foregoing description of the present invention provides
illustration and description, but is not intended to be exhaustive
or to limit the invention to the precise one disclosed.
Modifications and variations are possible in light of the above
teachings or may be acquired from practice of the invention. Thus,
it is noted that the scope of the invention is defined by the
claims and their equivalents.
* * * * *